Delivery of a therapeutic agent from an implantable medical device can be desirable for a variety of applications. Therapeutic agents can be released from a medical device, such as an expandable stent or valve, to treat or mitigate undesirable conditions including restenosis, tumor formation or thrombosis. Procedures for mitigating certain conditions can include implantation of a device comprising a therapeutic agent. For example, the implantation of stents during angioplasty procedures has substantially advanced the treatment of occluded body vessels. Angioplasty procedures such as Percutaneous Transluminal Coronary Angioplasty (PCTA) can widen a narrowing or occlusion of a blood vessel by dilation with a balloon. Occasionally, angioplasty may be followed by an abrupt closure of the vessel or by a more gradual closure of the vessel, commonly known as restenosis. Acute closure may result from an elastic rebound of the vessel wall and/or by the deposition of blood platelets and fibrin along a damaged length of the newly opened blood vessel. In addition, restenosis may result from the natural healing reaction to the injury to the vessel wall (known as intimal hyperplasia), which can involve the migration and proliferation of medial smooth muscle cells that continues until the vessel is again occluded. To prevent such vessel occlusion, stents have been implanted within a body vessel. However, restenosis may still occur over the length of the stent and/or past the ends of the stent where the inward forces of the stenosis are unopposed. To reduce this problem, one or more therapeutic agents may be administered to the patient. For example, a therapeutic agent may be administered systemically, locally administered through a catheter positioned within the body vessel near the stent, or coated on the stent itself.
A medical device can be coated with a therapeutic agent in a manner suitable to expose tissue near the implantation site of the medical device to the therapeutic agent over a desired time interval, such as by releasing the therapeutic agent from an implanted stent into surrounding tissue inside a body vessel. Various approaches can be used to control the rate and dose of release of therapeutic agents from an implantable medical device. The design configuration of an implantable device can be adapted to influence the release of therapeutic from the device. A therapeutic agent can be included in the implantable medical device in various configurations. In some devices, the therapeutic agent is contained within an implantable frame or within a coating on the surface of the implantable frame. An implantable frame coating can include a bioabsorbable material mixed with a therapeutic agent, or coated over the therapeutic agent. Some implantable medical devices comprise an implantable frame with a bioabsorbable material mixed with or coated over a therapeutic agent. For example, U.S. Pat. No. 5,624,411 to Tuch, filed Jun. 7, 1995, describes radially expandable stents coated with a porous polymer overlaying a first coating layer containing various bioactive agents. The porous polymer may be a biodegradable polymer, such as poly(lactic acid). Implantable medical devices can also comprise a porous biostable material containing a dissolvable material and a therapeutic agent, where dissolution of the removeable material upon implantation forms pores that release the therapeutic agent. For example U.S. Pat. No. 5,447,724 to Helmus, filed Nov. 15, 1993, describes a two-layer coating comprising an outer layer containing a mixture of a biostable polymer and an elutable component positioned over a bioactive reservoir layer such that the elutable component dissolves away upon implantation of the coating in a body, transforming the outer layer into a porous layer permitting diffusion of the bioactive agent from the reservoir layer through the outer layer and into the body.
The design of a controlled release medical device can also depend on the desired mode of implantation of the device. The device can be adapted to the appropriate biological environment in which it is used. For example, a device for percutaneous transcatheter implantation can be sized and configured for implantation from the distal portion of a catheter, adapted for expansion at the point of treatment within the body vessel by balloon or self-expansion. An implantable medical device can also be adapted to withstand a desired amount of flexion or impact, and should provide delivery of a therapeutic agent with a desired elution rate for a desired period of time.
There is a need for a medical device capable of releasing a therapeutic agent at a desired rate and over a desired time period upon implantation. Preferably, implantation of a medical device releases a therapeutic agent as needed at the site of medical intervention to promote a therapeutically desirable outcome, such as mitigation of restenosis. There is also a need for such a medical device with a releasable therapeutic agent capable of withstanding the flexion and impact that accompany the transportation and implantation of the device without releasing an undesirable amount of the therapeutic agent prior to implantation at a point of treatment. For example, a medical device can include a coating of a bioabsorbable material with sufficient durability to resist the undesirable premature release of the therapeutic agent from the device prior to implantation at a point of treatment within a body vessel.
Paclitaxel, and taxane analogues and derivatives thereof, can be used as a therapeutic agent coated on and released from implantable devices, such as stents, to mitigate or prevent restenosis. Paclitaxel is believed to disrupt mitosis (M-phase) by binding to tubulin to form abnormal mitotic spindles (i.e., a microtubule stabilizing agent).